Can the most commonly used antibiotics in the world manage morphine addiction by disrupting glutamatergic transmission? Recent evidence indicates that beta-lactam antibiotics are the only practical pharmaceuticals capable of directly increasing glutamate reuptake in the CNS. The mechanism is an increase in the expression and activity of GLT-1, the transporter protein responsible for 90% of glutamate reuptake in the mammalian brain. It is well known that GLT-1 transporter malfunction leads to an increase in extracellular glutamate which contributes to the perpetuation of morphine addiction by mediating the processes of morphine physical dependence and withdrawal. Therefore, one promising approach for managing this addiction is to increase the clearance of extracellular glutamate with drugs that activate GLT-1 transporters (e.g., beta-lactam antibiotics). The next step in establishing a new place in medicine for these antibiotics is to determine whether they actually inhibit the behavioral and neurochemical effects of morphine physical dependence and withdrawal in conscious animals. Results from experiments proposed herein will elucidate a role for beta-lactam antibiotics in the behavioral and neurochemical effects of morphine physical dependence and determine whether the antibiotics alter extracellular glutamate levels in morphine-na[unreadable]ve and morphine-dependent animals. The overall hypothesis to be tested is that beta-lactam antibiotics, in addition to activating GLT-1, decrease extracellular glutamate which prevents the development of morphine physical dependence. A multi-disciplinary approach will be taken to test this hypothesis with experiments proposed at the neurochemical and behavioral levels. The Specific Aims are: (1) To determine if morphine physical dependence and withdrawal are inhibited by repeated beta-lactam administration and (2) To determine, in morphine-na[unreadable]ve and morphine-dependent rats, if beta-lactam antibiotics decrease extracellular glutamate in brain regions that are known to mediate morphine dependence. The combined results from these studies will elucidate important interactions between beta-lactam antibiotics and glutamatergic systems as related to opioid addiction and delineate the effect of beta-lactam antibiotics on morphine-mediated behaviors. The Public Health Relevance: Morphine physical dependence is mediated in part by increased glutamatergic transmission in the brain. Because beta-lactam antibiotics are the only practical pharmaceuticals capable of directly increasing the cellular reuptake of glutamate in the brain, these widely used drugs may be useful in the clinical management of morphine addiction. The goal of this proposal is to determine if beta-lactam antibiotics, in addition to increasing glutamate reuptake, decrease morphine physical dependence in rats by disrupting glutamatergic transmission. [unreadable] [unreadable] [unreadable]